tbuckley/cabot-search huggingface dataset:
QOL-16. SYMON-SAYS (SYMPTOM MONITORING &amp; SYSTEMATIC ASSESSMENT AND REPORTING SYSTEM IN YOUNG SURVIVORS) PROGRAM HAS THE POTENTIAL TO DECREASE SYMPTOM BURDEN ON CHILDREN WITH CANCER
Authors: Jin-Shei Lai, Devin Peipert, Sally Jensen, Megan Urban, Stewart Goldman, Alicia Lenzen
Journal: Neuro-Oncology (2022)

Abstract AIMS The unrelieved symptoms and side effects of often-aggressive cancer treatments can lead to poor outcomes. SyMon-SAYS was developed to minimize symptom management barriers and symptom burdens by routinely collecting and interpreting patient-reported outcomes in pediatric oncology ambulatory settings. This paper reports the preliminary results of the 16-week SyMon-SAYS trial. METHODS Children (ages 8-17) with cancer (on-therapy or within 6-M post-treatment) were randomly assigned to either intervention (IG; weeks 1-16 intervention) or waitlist (WG; weeks 1-8 waitlist, weeks 9-16 intervention) group. Children in the intervention phase reported on 9 symptoms (fatigue, sadness, itch, pain, worry, appetite, nausea, sleep, headache) weekly via an electronic medical record patient portal. Scores exceeding a pre-defined threshold triggered an alert to the treatment team. Parents completed a symptom management barriers questionnaire (SMBQ) at baseline, weeks 8 (primary time-point and analyzed in this paper) and 16. Mixed-effects models were used to evaluate symptom burden over time. RESULTS Data from 75 children (37 IG, 38 WG) were analyzed (mean age=13.3 years, 58.8% male, 74.7% white). Of them, 43.9% had leukemia, and 17.5% brain tumor. On average, the IG completed 11 (possible min=0 max=16) and the WG completed 5 (possible min=0 max=8) symptom checklists; of them, 60% triggered symptom alerts. Results of the mixed-effects models showed significantly (p&amp;lt; 0.05) improvement in fatigue, sadness, worry, appetite and headache. No significant changes were found on others. For SMBQ, IG parents reported significantly in favor of “enough time with my child's doctors/nurses to talk about symptoms” than WG parents from baseline to week 8. No significant differences between IG and WG over time on other SMBQ items. CONCLUSIONS Our preliminary findings showed SyMon-SAYS alleviated emotional related symptoms over time. Physical symptoms might be related more to disease severity and treatment intensity, which we plan to investigate when more data is available.
NCOG-38. PEMBROLIZUMAB (ANTI-PD-1) INDUCED LIMBIC ENCEPHALITIS PRESENTING AS EPISODIC APHASIA
Authors: Anza Zahid, Meryim Poursheykhi, Ivo W Tremont
Journal: Neuro-Oncology (2022)

Abstract PD-1 immune checkpoint inhibitors (ICI) have been associated with neurological immune-related adverse events including meningioencephalitis and limbic encephalitis that can manifest as paraneoplastic syndromes. We present a case of pembrolizumab (Anti-PD-1) induced limbic encephalitis presenting as episodic aphasia. A 62-year-old man with poorly differentiated papillary thyroid carcinoma with extensive brain, lung, lymphatic metastases, post total-thyroidectomy, radioiodine therapy, chemotherapy with dabrafenib and trametinib, and stereotactic radiation presented with recurrence of brain metastasis 1 year after diagnosis of a 2.1 cm metastatic lesion in the left parieto-occipital region. The metastases had initially improved in size and number with radiation, followed on serial MRI Brain - that were stable. Biopsy of recurrence revealed a poorly differentiated cancer. He was subsequently treated with pembrolizumab for 6 months for refractory carcinoma. Two months after treatment initiation, he reported episodic behavioral arrest, confusion, and expressive aphasia, initially concerning for seizures. Continuous EEG monitoring revealed non-epileptogenic left-sided foci and no seizures were captured. Patient empirically started on levetiracetam and clobazam - however, episodes persisted. Lumbar puncture revealed lymphocytic pleocytosis (10-14 cells), elevated protein (48-68 mg/dL), negative cytology, flow cytometry, and viral studies including JC virus. Paraneoplastic panel in serum and cerebrospinal fluid were negative. Repeat MRI findings were most consistent with radionecrosis and on contrary improvement of the previous metastatic lesions. This rose suspicion for pembrolizumab-induced encephalitis and he received high dose steroids with minimal response but great clinical improvement with IVIG and induction/maintenance therapy with rituximab. Marked reduction in aphasic episodes were noticed thereafter. PD-1 ICI-related encephalitis is diagnosis of exclusion that should be considered in patients with encephalopathy or neurological deficit following 3 months of treatment initiation and response to immunosuppressive therapy. Higher incidences reported in males. Early recognition is crucial to prevent long-term neurological damage. Outcomes depend on patient characteristics and timeline of presentation.
NIMG-96. SPINAL MENINGEAL MASS LESION: A RARE PRESENTATION OF FOLLICULAR LYMPHOMA
Authors: Jessica White, Michelle Clarke, Jonas Paludo, Ugur Sener
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE We aim to describe a case of follicular lymphoma that presented as a durally-based thoracic spine lesion manifested as rapidly progressive back pain and meningismus. BACKGROUND Follicular lymphoma is one of the most common forms of non-Hodgkin’s lymphoma; however, it is rare for follicular lymphoma to present as a spinal meningeal mass lesion. METHODS This is a case report and review of literature. RESULTS A 38-year-old man developed thoracic back pain that progressed over one month with associated severe focal tenderness over his mid to lower thoracic spine. He developed intermittent numbness of the bilateral lower extremities, nuchal rigidity, difficulty sleeping, and night sweats. An MRI of the thoracic spine demonstrated a dorsal intradural, extramedullary enhancing lesion from T6-T9 extending outside the spinal canal. Dural thickening across the entire circumference of the spinal cord was noted. CT-guided biopsy of the thoracic lesion was performed, and pathology was consistent with follicular lymphoma. FDG PET: CT demonstrated no systemic disease. Bone marrow biopsy was negative for malignancy. Symptoms resolved with dexamethasone therapy. He was treated with bendamustine and rituximab with follow up PET: CT two months later demonstrating a complete response. DISCUSSION This case illustrates an unusual presentation of follicular lymphoma as a spinal meningeal mass lesion. Though rare, lymphoma should be included in the differential diagnosis of a dural mass lesion. Prompt diagnosis and initiation of treatment can lead to complete response and resolution of symptoms.
EXTH-73. A NOVEL ANTI-GALECTIN-3 MONOCLONAL ANTIBODY THERAPEUTIC DIMINISHES MIGRATION AND SLOWS TUMOR GROWTH TO PROLONG SURVIVAL IN GLIOBLASTOMA
Authors: Anne Marie Barrette, Krutika Deshpande, Marvin Cadiente, Xi Wang, Dongxu Sun
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most aggressive, invasive, and malignant primary brain cancer with a standard of care that hasn’t been improved in over 15 years. Heterogenous tumor cell populations that evade resection and develop resistance to chemoradiation highlight the need for novel therapies that can target both the migratory and proliferative nature of GBM cells. Galectin-3, a carbohydrate-binding protein overexpressed in the GBM parenchyma and stromal astrocytes and microglia/macrophages, is a potent modulator of cell proliferation, migration, angiogenesis, T-cell inhibition, and M2 macrophage polarization. Increased Galectin-3 expression levels correlate to lower survival in glioma patients, and these levels further increase following exposure to temozolomide or radiation alone or in combination, thus more greatly emphasizing the need to target Galectin-3 in GBM patients following initial standard-of-care treatment. Here, we characterize the therapeutic effects of a monoclonal anti-Galectin-3 antibody (Gal3 Ab) we have developed for its ability to inhibit GBM tumorigenic and metastatic potential in several in vitro assays and in vivo heterotopic and orthotopic mouse models. We find that Galectin-3 directly binds to EGFR, the most commonly amplified gene locus in GBM affecting roughly 40% of patients, and our Gal3 Ab can block this binding. Human GBM cells treated with Gal3 Ab show a significant decrease in migration and invasion and reduction in EGFR activation in vitro. In vivo, the Gal3 Ab additionally decreases tumor burden and provides a survival benefit in combination with temozolomide compared to the current standard-of-care treatment alone. Our studies indicate the potential for our novel anti-Galectin-3 antibody to further benefit GBM patients receiving chemoradiation treatment by diminishing tumor cell migration and slowing tumor growth.
BIOM-10. CIRCULATING EXTRACELLULAR VESICLES AS A TOOL FOR DIAGNOSIS, PROGNOSIS AND MONITORING IN GLIOMA
Authors: Franz Ricklefs, Kathrin Wollmann, Cecile Maire, Richard Drexler, Manfred Westphal, Katrin Lamszus, Lasse Dührsen
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE Extracellular vesicles (EVs) represent a population of lipid bilayer nanoparticles released by all cell types, including tumor cells that can serve as a noninvasive source for liquid biopsy. To date, MRI images have been the established method for monitoring treatment efficacy in brain tumor patients. We investigated the potential of pure EV count for diagnosis, prognosis, and treatment monitoring in gliomas. METHODS Plasma samples, differential blood counts, at multiple timepoints before and after surgery of glioblastoma patients (n=101) were collected. Follow-up samples were obtained every 3 months. Healthy donors served as controls (n=29). Plasma EVs concentration was measured by Nanoparticle Tracking Analysis (NTA). EVs were characterized by electron microscopy and imaging flow cytometry. Tumor burden was measured by MRI images. Clinical characteristics were prospectively recorderd. In addition plasma EVs from Mut3 tumor bearing mice were analysed at d3, d5, d7, d10, d12 after tumor injection (n=20). MRI images and differential blood counts were analyzed. RESULTS Glioblatoma patients have a 5-fold increase of plasma EVs compared to HD; p &amp;lt; 0.0001). Circulating EVs counts correlated only with FLAIR hyperintensity and with no other MRI or blood-based parameter. Similar results were obtained from Mut3 tumor mice. Dichotomisation of GBM patients in EVhigh and low revealed a significant overall survival and progression free survival benefit for EVlow patients (p=0.004). After surgery, EVs decreased significantly (5-fold, p&amp;lt; 0.0001). A massive drop in EVs was associated with gross-total resection (p &amp;lt; 0.05). At the time of tumor recurrence, the number of circulating EVs increased in all patients during a follow-up (9 months). CONCLUSION Our findings highlight the potential of circulating EVs as a biomarker tool for diagnosis, prognosis and treatment monitoring in GBM patietns, as they seem to reflect the presence of a tumor mass and thus may assist in clinical decision making.
NCMP-15. A CASE OF SYSTEMIC METASTATIC DIFFUSE LEPTOMENINGEAL GLIONEURAL TUMOR
Authors: Sahithi Battini, Erika Horta, Murat Gokden, Viktoras Palys
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Diffuse leptomeningeal glioneural tumor (DLGT) is a very rare central nervous tumor that has no standard of care for its treatment. This report illustrates a case of DLGT with a unique presentation and a first description of multiple systemic metastasis. Case: 19 year-old male with personal history of hereditary multiple osteochondromas and recent covid-19 infection who on investigation of headaches, progressive cranio-neuropathies, and right-sided weakness was found to have vasospasms resulting in acute infarcts in multiple vascular areas, and diffuse leptomeningeal enhancement in the thoracic spine and cauda equina. Patient underwent meningeal biopsy, after 2 months of first symptoms, which revealed DLGT per two different neuro-oncology centers. Course of disease was complicated with hydrocephalus needing shunt placement soon after diagnosis. Craniospinal radiation concurrent with temozolomide was started one month from diagnosis. Patient developed pancytopenia and chemotherapy was stop in the first weeks during radiation therapy. Metastatic disease to bone marrow was diagnosed in the second adjuvant temozolomide cycle through biopsy. One week after, on investigation of pleural effusion, lung metastasis were discovered on pleural cytology and thoracic computer tomography. Liquid biopsy showed non-actionable mutations on PIK3CA, BRAF and KRAS. Chemotherapy with carboplatin and vincristine was started with markedly improvement of pancytopenia and pleural effusions leading to cessation of frequent transfusions and auxiliary oxygen. Vincristine dose was decreased due to painful neuropathy and tinnitus. At the end of endovenous chemotherapy, worsening of disease was found with metastasis to muscles of the face and brain parenchyma. Patient was then enrolled in hospice, dying weeks after. CONCLUSION DLGT should be considered in the differential diagnosis of vasospasm. DLGT is a primary central nervous system that can metastasize to other organs. Although no standard of care is yet identified, chemotherapy with vincristine and carboplatin can be offered to systemic metastatic disease.
RADT-27. FRACTIONATED RADIOTHERAPY AS FIRST-LINE TREATMENT FOR INTRACRANIAL MENINGIOMAS
Authors: Justin Wang, Alexander Landry, Farshad Nassiri, Grace Lee, Lauren Rogers, Jeffrey Zuccato, Mathew Voisin, David Munoz, Derek Tsang, Normand Laperriere, Gelareh Zadeh
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Meningiomas are the most common primary brain tumour, and patients requiring intervention typically undergo surgical resection as first-line therapy. However, fractionated radiotherapy (fRT) as primary treatment remains an option for patients with larger tumours and surgical contraindications, although outcome prediction in this group remains uncertain. We aimed to assess the clinical factors that contribute to treatment failure in a cohort of meningiomas treated with fRT as first-line therapy. METHODS Patients treated with primary fRT for intracranial meningiomas at our institution from November 1, 1998 to December 30, 2017 were reviewed. Those who received upfront surgical resection, radiosurgery, or had less than 6 months of clinical follow up were excluded. We applied logistic regression and Cox regression analysis to ascertain key predictors of treatment failure, progression-free survival (PFS), and adverse events following radiotherapy. RESULTS Our cohort included 147 tumours, of which 25 progressed after fRT (median PFS of 3.45 years). Tumours that progressed following RT had a larger median gross tumour volume (GTV) than those that did not (32.3cm3 vs 20.2cm3,p = 0.03768). Pre-RT GTV greater than 11.27cm3 was independently predictive of treatment failure. Larger pre-RT GTV was also associated with significant (grade 3/4) adverse events following fRT. Finally, cerebellopontine angle meningiomas were more prevalent in the group that progressed (20% vs 3.3%, p = 0.0046), whereas cavernous sinus and optic nerve sheath meningiomas had longer PFS (p = 0.0067). CONCLUSION We present the largest known cohort of meningiomas treated with fRT as first line therapy and find pre-RT tumour GTV and location to be the critical predictors of outcome, adding to the discussion of treatment considerations in this heterogeneous disease.
DDEL-19. TREATMENT ADHERENCE OF SELUMETINIB AMONG PATIENTS DIAGNOSED WITH NEUROFIBROMATOSIS TYPE I AND PLEXIFORM NEUROFIBROMA IN THE UNITED STATES
Authors: Xiaoqin Yang, Chi Gao, Sama Ahsan, Theresa Dettling, Yuqian Gu, Azeem Banatwala, Wendy Cheng
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Selumetinib is the only FDA-approved (April 2020) treatment for pediatric patients with neurofibromatosis type 1 (NF1) and symptomatic inoperable plexiform neurofibroma (PN). Real-world information on selumetinib treatment patterns is lacking. Our study assessed treatment adherence among pediatric patients prescribed selumetinib using a large health claims database. METHODS Eligible patients aged 2-21 years with ≥ 1 selumetinib prescription fill in 4/2019-1/2022 (1st fill defines index date), ≥ 6 months of eligibility pre index (baseline), ≥ 3 months of eligibility post index (observation period) and no clinical trial participation were identified from the Clarivate® DRG® Real World Data Repository. Baseline patient characteristics were summarized. Adherence to selumetinib during observation period was evaluated using medication possession ratio (MPR) among patients with ≥ 2 prescription fills and proportion of days covered (PDC) over fixed time periods. Proportion of adherent patients (≥ 80% MPR or PDC) were reported. RESULTS 73 eligible patients were identified with mean age of 13.0 (standard deviation [SD]: 4.7) years, 54.8% male, 65.8% with commercial insurance, and 31.5% with Medicaid. The most common baseline treatment was pain medication (23.3%). The mean (SD) Quan Charlson Comorbidity Index was 0.9 (1.3) and the most common NF1 PN-related comorbidities were attention-deficit hyperactivity disorder (11.0%) and headaches (6.8%). The mean (SD) MPR was 86.0% (19.8%) and 71.2% of patients were adherent (MPR ≥ 80%). At 60, 90 and 120 days, the mean PDC was 79.6%, 73.0% and 68.4%, respectively; and the proportion of adherent patients (PDC ≥ 80%) was 56.2%, 56.2% and 48.6%, respectively. Analyses assessing PDC at 150 and 180 days indicated slightly under half of patients remained adherent. CONCLUSION Mean adherence to selumetinib was high; about half to three-quarters of NF1 PN pediatric patients were adherent to selumetinib--a clinically important finding given the generally low medication adherence rates in pediatric patients.
CNSC-18. HYPOXIA-INDUCED METABOLIC ADAPTATIONS THROUGH ACOX-1 IN GLIOBLASTOMA
Authors: Ayon Bhattacharya, Laura Caflisch, Henriette Balinda, Andrew Boyer, Alessia Lodi, Mei Zhou, Mengxing Li, Jennifer Chiou, Renu Pandey, Stefano Tiziani, Ratna Vadlamudi, Andrew Brenner
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Hypoxia is a major driver of invasiveness and resistance in glioblastoma (GBM). We hypothesize that GBM adapts to chronic hypoxic conditions through utilization of peroxisomal fatty acid oxidation (FAO). We explored the contribution of acyl coenzyme A oxidase 1 (ACOX-1), a rate-limiting enzyme for peroxisomal FAO, in metabolic adaptation to hypoxia and as a potential therapeutic target. METHODS A primary cell line from a bevacizumab-resistant tumor (012015) was cultured under chronic hypoxia (2%O2) or normoxia (21% O2). We used UPLC-MS/MS and GC-MS to determine lipid and polar metabolites. RNA seq was performed on U251 ACOX-1 (KO) cells under normoxic and hypoxic conditions. Differential gene expression was obtained using TopHat2 (genome alignment), HTSeq, and DEseq. Gene set enrichment analysis was used to compare biological pathways between conditions. ACOX-1 was deleted using CRISPR-Cas9 and orthotopically implanted in NCr/SCID nude mice. Animals were treated with 30 mg/kg of pazopanib or vehicle daily through oral gavage. RESULTS In 012015 cells we observed altered carnitine metabolites, increase in specific triglycerides, and S-lactoylglutathione indicating dysfunctional mitochondrial FAO, and increase in oxidative stress between hypoxic and normoxic conditions. Also, decrease in citric acid cycle metabolites, increase in glycolytic metabolites were seen in hypoxia. Further RNA seq on U251 ACOX-1 (KO) cells showed downregulated genes such as PCK1, SCD, SREBF1, PIPOX (p&amp;lt; 1E-8) and significant KEGG pathways such as unsaturated fatty acid (p= 0.009), peroxisome (p= 0.025) and PPAR (p= 0.016) between hypoxia and normoxia suggesting increased dependence of these cells on peroxisomal FAO. ACOX-1 (KO) mice showed increased survival when treated (p= 6.7E-04) with pazopanib. CONCLUSION In ACOX-1 (KO) model, we observed metabolomic reprogramming with downregulated genes, dysregulated metabolites, and pathways in peroxisomal FAO in hypoxia. These identified genes could be potential targets for therapy in combination with anti-angiogenic therapies that increase hypoxia in GBM.
TMIC-16. INTRATUMORAL THROMBOSIS INITIATES HYPOXIA AND NECROSIS TO DRIVE TUMOR PROGRESSION THROUGH DRAMATIC TUMOR MICROENVIRONMENTAL ALTERATION
Authors: Steven Markwell, Cheryl Olson, Jiabo Li, Ling-Kai Shih, James Ross, Daniel Brat
Journal: Neuro-Oncology (2022)

Abstract All GBM molecular subsets share the common trait of accelerated progression following necrosis which cannot be adequately explained by cellular proliferation arising from accumulated genetic alterations. We suggest that development of necrosis is much more than a passive phenomenon related to rapid growth but rather is a driving force behind TME restructuring responsible for sustaining accelerated expansion. Current tumor models fail to adequately mimic the magnitude of post-necrotic restructuring within the microenvironment and remain overly reliant on post-mortem analyses, obligating researchers to extrapolate causal relationships between necrosis and progression phenomena during tumor evolution. In GBM (WHO grade 4), the most malignant primary brain tumor, vascular pathology and central necrosis precede rapid, radial expansion. Mechanisms enabling selective fitness within a hypoxic/anoxic GBM setting remain poorly understood. Nanostring GeoMX spatial profiling demonstrates M1-like TAM enrichment in non-necrotic human samples and M2-like TAMs in perinecrotic regions. Our immunocompetent RCAS/tv-a model aptly captures events seen in human gliomas, exposing dynamic temporal and spatial changes that facilitate GBM progression, incorporating unique microenvironmental stressors typically absent from GBM animal models, specifically emerging central necrosis. Simultaneously, our in vitro models scrutinize how hypoxia-dependent signaling between GBM cells, microglia and monocytes alter TAM accumulation and function in the TME. TAMs increase dramatically with the onset of necrosis, with a preferential localization to the hypoxic zone in the perinecrotic niche, which supports their survival. Flow cytometry on digested pre- and post-necrotic GBMs, showed increased TAM accumulation at 6 weeks vs. 2 weeks (necrosis emerges in week 4-5). Our in vivo data along with in silico analysis of Ivy GAP and TCGA datasets suggests GBM cells within the peri-necrotic niche attract and polarize TAMs through MIF secretion, necrotic DAMP (adenosine, S100B) release, and arginase secretion to suppress T cells.